Production method of nasal drop composition, and nasal drop composition

ABSTRACT

Provided are: a method for producing a nasal drop composition suitable for treatment or prevention of a disease or symptom in the nasal cavities; and a nasal drop composition produced by the production method. The nasal drop composition production method characterized by including a mixing step of mixing earthworm castings with water and a collecting step of collecting vaporized water generated from a mixture obtained in the mixing step to obtain a liquid; and the nasal drop composition produced by the production method. It is preferred to further mix an organic substance together with the earthworm castings and

TECHNICAL FIELD

The present invention relates to: a method for producing a nasal dropcomposition suitable for treatment or prevention of a disease or symptomin the nasal cavities; and a nasal drop composition produced by theproduction method.

BACKGROUND ART

Conventionally, a nasal drop composition is used for treatment orprevention of pollinosis and empyema. Nasal drop compositions have beenvariously studied (for example, Patent Documents 1 and 2), but,generally speaking, a nasal drop composition different from conventionalones is demanded due to difficulties in obtaining a desired effectaccording to a target.

RELATED ART DOCUMENTS Patent Document

Patent Document 1 JP4591810B2

Patent Document 2 JP4790096B2

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

In these situations, an object of the present invention is to provide: amethod for producing a nasal drop composition suitable for treatment orprevention of a disease or symptom in the nasal cavities; and a nasaldrop composition produced by the production method.

Means for Solving the Problems

The present inventors intensively studied to solve the above-describedproblems and consequently discovered that, a liquid obtained bycollecting vaporized water generated upon mixing of earthworm castingswith water is suitable for treatment or prevention of a disease orsymptom in the nasal cavities, thereby completing the present invention.

Namely, a nasal drop composition production method according to thepresent invention is characterized by including: a mixing step of mixingearthworm castings with water; and a collecting step of collectingvaporized water generated from a mixture obtained in the mixing step toobtain a liquid.

In the nasal drop composition production method according to the presentinvention, it is preferred to further mix an organic substance togetherwith the earthworm castings and the water in the mixing step.

In the nasal drop composition production method according to the presentinvention, it is preferred that the organic substance is a woodmaterial.

It is preferred that the nasal drop composition production methodaccording to the present invention further includes a diluting step ofdiluting the liquid obtained by the collection of the vaporized water inthe collecting step with water.

A nasal drop composition according to the present invention ischaracterized by being produced by the nasal drop composition productionmethod.

It is preferred that the nasal drop composition according to the presentinvention is used in the form of mist.

It is preferred that the nasal drop composition according to the presentinvention is for treatment or prevention of a disease or symptom in thenasal cavities.

In the nasal drop composition according to the present invention, it ispreferred that the disease or symptom in the nasal cavities ispollinosis or empyema.

A method of treating pollinosis or empyema according to the presentinvention is characterized by administering the nasal drop compositionto a patient.

It is preferred that the nasal drop composition according to the presentinvention is for use in the treatment of pollinosis or empyema.

Effects of the Invention

According to the present invention, it is possible to provide: a methodfor producing a nasal drop composition suitable for treatment orprevention of a disease or symptom in the nasal cavities; and a nasaldrop composition produced by the production method.

Mode for Carrying Out the Invention

The nasal drop composition production method according to the presentinvention is characterized by including: a mixing step of mixingearthworm castings with water; and a collecting step of collectingvaporized water generated from a mixture obtained in the mixing step. Inthe mixing step, it is preferred that an organic substance is furthermixed together with the earthworm castings and the water. Althoughdetails about the mechanism is not known clearly, it is believed thatmicroorganisms such as bacteria contained in earthworm castingsdecompose and ferment organic substances contained in the earthwormcastings and organic substances added separately to the earthwormcastings and, as a result, a liquid obtained by collecting the vaporizedwater is effective for treatment or prevention of a disease or symptomin the nasal cavities.

Hereinbelow, the nasal drop composition production method and the nasaldrop composition according to the present invention will be described indetail.

[Nasal Drop Composition Production Method]

(Mixing step)

The mixing step is a step of mixing earthworm castings with water.

The earthworm castings are not particularly limited, and castings ofearthworms Lumbricus rubellus, Lumbricus terrestris (LT), Eiseniafoetida, Allolobophora caliginosa, Dendrobaena octaedra, Allolobophorajaponica Michaelsen, Drawida hattamimizu Hatai, Pheretima divergensMichaelsen, Pheretima communissima, Pheretima agrestis, Pheretimasieboldi Horst, Pheretima hilgendorfi, Pontodrilus matsushimensisIizuka, Tubifex hattai Nomura, and Limnodrilus gotoi Hatai (=L. socialisStephenson) can be used.

The water to be mixed with the earthworm castings is not particularlylimited, and tap water and distilled water can be used. The water may bepurified with a filtration material, a reverse osmosis membrane or thelike. From the viewpoint of the removal of microorganisms such asbacteria, it is preferred to use a microporous filtration material, amicroporous reverse osmosis membrane or the like. For example, an SPG(Shirasu porous glass) permeable membrane can be used preferably.

The mixing ratio of the earthworm castings and the water is preferably0.05 to 20 L, more preferably 0.1 to 10 L, still more preferably 0.2 to5 L, particularly preferably 0.5 to 2 L of the water with respect to 1kg of the earthworm castings.

In the mixing step, it is preferred that an organic substance is furthermixed together with the earthworm castings and the water. When anorganic substance is mixed, a nasal drop composition more excellent inthe effect of treating or preventing a disease or symptom in the nasalcavities can be obtained, and the pH value of the nasal drop compositioncan be controlled. The organic substance is not particularly limited, aslong as the organic substance can be decomposed when mixed with theearthworm castings, but for example, an organic substance derived from aliving organism such as an animal, a plant, a bacterium or a protozoancan be used. Specific examples of a plant-derived organic substanceinclude: a wood material such as wood chips, wood dusts and rice hulls;a mushroom bed for use in the culturing of mushrooms; and the like. Tomix a wood material as the organic substance is preferred, because anodorless liquid is likely to be collected in the collecting step. As thewood material, wood chips are preferred. The species of the wood is notparticularly limited, and examples thereof include a conifer tree suchas yew, Japanese torreya, Japanese cypress, hiba arborvitae, Japanesecedar, Japanese umbrella pine, pine, Japanese Douglas fir, hondo spruce,fir, hemlock fir, or sequoia, or a broadleaf tree such as Japanesecherry, oak, zelkova, beech, birch, chinquapin, maple, alder, Japaneselinden, Japanese hornbeam, or bamboo. Among the wood, wood of Pinalescan suitably be used. More preferably, wood of Cupressaceae can be used,still more preferably, wood of Taxodioideae can be used, andparticularly preferably, wood of Cryptomeria can be used.

The mixing ratio of the earthworm castings and the organic substance ispreferably 0.05 to 20 kg, more preferably 0.1 to 10 kg, still morepreferably 0.2 to 5 kg, and particularly preferably 0.5 to 2 kg of theorganic substance with respect to 1 kg of the earthworm castings.

The mixing method to be employed in the mixing step is not particularlylimited, and it is preferred that the mixture is fully mixed by stirringor the like. The order in which the components are mixed is notparticularly limited. For example, it is possible to introduce theearthworm castings and the organic substance into a vessel andsubsequently add water thereto, and it is also possible to introduce theorganic substance into a vessel, subsequently add water thereto, andsubsequently add the earthworm castings thereto.

It is not necessary to mix the whole amounts of the components at once,but each of the water, the earthworm castings and/or the organicsubstance may be added in divided several portions during the mixing.Adding each component in several portions is preferred, because it ispossible to continuously collect vaporized water while replenishing thewater that is reduced by vaporization and the earthworm castings or theorganic substance that is reduced by decomposition.

In addition, the fermentation is further stabilized after a lapse oftime from the first mixing procedure. Therefore, it is preferred tocollect the vaporized water, for example, after a lapse of about 1 dayto obtain a liquid excellent in an effect of treatment or prevention ofa disease or symptom in the nasal cavities. From this view point, it ispreferred to continuously collect the vaporized water while replenishingthe components in several portions.

Heat is generated in the mixture as the result of the fermentation ofthe earthworm castings and the separately added organic substance.However, at some air temperatures, it is preferred to mix the componentswhile heating. When heating the mixture, it may be heated, for example,to 30 to 50° C.

(Collecting Step)

The collecting step is a step of collecting vaporized water generatedfrom the mixture obtained in the mixing step to obtain a liquid(hereinafter, also referred to as “aqueous organic substancedecomposition product”). The collecting step may be carried out whilecarrying out the mixing step.

In the collecting step, vaporized water generated in a temperature rangerising due to a fermentation heat (reaction heat) generated as a resultof the fermentation of the mixture can be collected, and it is notnecessary to heat the mixture up to the boiling point. Depending on thetemperatures, it is preferred to mix the components while heating. Whenheating the mixture, it may be heated, for example, to 30° C. to 50° C.

The method for the collecting is not particularly limited, as long asvaporized water can be collected. For example, vaporized water may becollected with a dehumidifier. As the dehumidifier, a cooling-modedehumidifier, a compression-mode dehumidifier or the like can be used.It is preferred to collect vaporized water without boiling the mixture.

The method for making the collected vaporized water into a liquid is notparticularly limited. For example, when the vaporized water is collectedwith a dehumidifier, an aqueous organic substance decomposition productcan be obtained. The dehumidifier is not particularly limited, as longas the vaporized water can be collected in a liquid form. For example, acooling-mode dehumidifier, a compression-mode dehumidifier or the likecan be used.

The pH value of the liquid obtained by the collection of the vaporizedwater is preferably 5 to 9, more preferably 6 to 8, still morepreferably 6.5 to 7.5.

(Diluting Step)

The aqueous organic substance decomposition product obtained by thecollection of the vaporized water in the collecting step may be used asthe nasal drop composition without any modification. However, it ispreferred to use the aqueous organic substance decomposition product ina diluted form. A solvent to be used for the dilution may be water, andtap water and distilled water can be used. The water to be used for thedilution may be purified with a filtration material, a reverse osmosismembrane and the like. From the viewpoint of the removal ofmicroorganisms such as bacteria, it is preferred to use a microporousfiltration material, a microporous reverse osmosis membrane or the like,and an SPG (Shirasu porous glass) permeable membrane is preferably used.In the case where the aqueous organic substance decomposition product isdiluted, the dilution may be carried out at a dilution factor of, forexample, 1.5 to 10 times, preferably 4 to 6 times, more preferably 4.5to 5.5 times.

[Nasal drop composition]

A nasal drop composition according to the present invention ischaracterized by being produced by the nasal drop composition productionmethod according to the present invention. The nasal drop compositionaccording to the present invention is not particularly limited as longas the nasal drop composition is produced by the nasal drop compositionproduction method according to the present invention and is effectivefor treatment or prevention of a disease or symptom in the nasalcavities, and is preferably in a liquid form. Alternatively, the liquidnasal drop composition may be sprayed or evaporated in the form of mist.Furthermore, the nasal drop composition may be processed into a solidform such as gel, powder, granule or the like by mixing with, forexample, an excipient or the like.

The nasal drop composition of the present invention may contain apharmaceutically acceptable carrier. As a pharmaceutically acceptablecarrier, an excipient, a binder, a disintegrant, a fluidizing agent, alubricant, a coating agent, a suspending agent, a coloring agent, asweetening agent, a surfactant, or the like can be used, and thecomposition can be made in the form of a general pharmaceuticalpreparation according to a known method. The composition may alsocontain another therapeutic/prophylactic ingredient or apharmaceutically acceptable additive.

In the nasal drop composition of the present invention, the blendingamount of the liquid collected in the collecting step may be an amountto be effective according to each purpose. An appropriate blendingamount depends on various factors such as a purpose, a form, productionconditions and the like, and for example, in the case of a liquid nasaldrop composition, the amount of the liquid collected in the collectingstep may be 5% by volume or more, preferably 5 to 50% by volume, morepreferably 10 to 40% by volume, and still more preferably 20 to 30% byvolume.

The amount of the nasal drop composition of the present invention to beused also may be an amount effective for the purpose. The appropriateamount to be used depends on various factors such as a purpose, a form,production conditions, symptoms, and the like, and, for example, when aliquid nasal drop composition is used by spraying in the form of mist inthe nasal cavities, spraying may be performed 6 to 10 times per day.

The nasal drop composition of the present invention is preferably usedfor treatment or prevention of a disease or symptom in the nasalcavities. The disease or symptom in the nasal cavities is notparticularly limited, and examples thereof include pollinosis andempyema.

In the nasal drop composition according to the present invention, otheractive ingredients and known conventional additives usable in nasal dropcompositions (e.g., a coloring agent, a fragrance, an antioxidant agent,an ultraviolet ray absorber, a chelating agent, a surfactant, aviscosity modifier, a pH modifier, a thickening agent, an antifoamingagent, a preservative agent, an bactericidal/antibacterial agent, adispersant and an organic solvent) may be added, as long as theadvantageous effects of the present invention cannot be deteriorated.

The nasal drop composition of the present invention may contain drypowder, milled matter and/or extract of earthworm. By mixing dry powder,milled matter, and/or extract of earthworm, it is possible to obtain aliquid more excellent in the effect of treatment or prevention of adisease or symptoms in the nasal cavities. Among these, an extract ofearthworm is more preferable, since a more excellent effect can beobtained. As the earthworm extract, an extract extracted from a driedearthworm powder with water, ethanol or an aqueous ethanol solution canbe used, for example.

Earthworms used as a raw material are not particularly limited, and, forexample, Lumbricus rubellus, Lumbricus terrestris, Eisenia foetida,Allolobophora caliginosa, Dendrobaena octaedra, Allolobophora japonicaMichaelsen, Drawida hattamimizu Hatai, Pheretima divergens Michaelsen,Pheretima communissima, Pheretima agrestis, Pheretima sieboldi Horst,Pheretima hilgendorfi, Pontodrilus matsushimensis Iizuka, Tubifex hattaiNomura, Limnodrilus gotoi Hatai (=L. socialis Stephenson), or the likecan be used.

The dry earthworm powder herein means powder obtained by drying a milledmatter or extract of untreated or pretreated earthworms. The milledmatter of earthworms is a liquid or paste-like one obtained by millinguntreated or pretreated earthworms. The extract of earthworms means anextract obtained by dissolving untreated or pretreated earthworms ormilled matter thereof in water or an organic solvent and by removing orseparating an insoluble fraction therefrom. The pretreatment is notparticularly limited, and examples thereof include a removal treatmentof dirt or the like described below. The dry powder, milled matter, andextract of earthworm may be subjected to post-treatment, and examples ofthe post-treatment include granulation, filtration, purification,concentration, dilution, and pH adjustment.

The milling method for obtaining milled earthworms is not particularlylimited, and earthworms can be ground using a homogenizer, a blender, ahomomixer, a grinder, a Dounce homogenizer, or the like.

An extraction method for obtaining an extract of earthworms is notparticularly limited, but, for example, an extraction can be extractedby dissolving dry powder or a milled matter of earthworms in anextraction solvent and by removing or separating an insoluble fractiontherefrom. Examples of the extraction solvent include water, an aqueoussolution and an organic solvent such as ethanol, acetone or ethylacetate, and the extraction solvent may be used singly or two or morethereof may be used in combination. Among them, water, ethanol oraqueous ethanol solution is preferable.

A drying method for obtaining a dried earthworm is not particularlylimited, and the dried earthworm can be obtained by a drying method suchas freeze drying, heat drying, or spray drying. Among them, the freezedrying is preferred for the reasons described below.

It is preferable to remove contents remaining in the gastrointestinaltract of an earthworm, dirt adhering to a skin thereof and the like. Theremoval method is not particularly limited, and a known method may beused for removal. For example, a method in which an earthworm isimmersed in an aqueous solution of an alkaline salt such as sodium saltor potassium salt to discharge contents in the gastrointestinal tract(the method described in JP Nos. H01-47718A, H01-47719A, H01-47720A, orH01-268639A), a method in which an earthworm is allowed to stand in anacid aqueous solution maintained at 6 to 26° C. for 0.1 to 5 hours toremove contents in the gastrointestinal tract (the method described inJP No. H03-72427A), or the like may be employed.

As such a removal method, it is preferable to bring an earthworm intocontact with a chloride of a metal described below and/orhydroxycarboxylic acid.

A chloride of the metal is a chloride of at least one metal selectedfrom the group consisting of potassium, sodium, magnesium and calcium.In other words, the chloride of metal is at least one selected from thegroup consisting of potassium chloride, sodium chloride, magnesiumchloride and calcium chloride. A mixture of these may also be used or amixture of these with other harmless components that can be added tofood may be used. Examples of such a mixture include salt, rock salt andsolar salt. A chloride of the above-described metal can be used bysprinkling in a powdery form on a living earthworm, whereby theearthworm is in contact with the metal chloride.

It is preferable to bring a living earthworm into contact withhydroxycarboxylic acid as described below after bringing the livingearthworm into contact with a chloride of the above-described metal. Itis also possible to bring the earthworm into contact withhydroxycarboxylic acid as described below without contacting theearthworm with a chloride of the above-described metal.

The contact with hydroxycarboxylic acid can also be carried out bysprinkling powdery hydroxycarboxylic acid on living earthworms. Theliving earthworms may be immersed in a hydroxycarboxylic acid aqueoussolution having a pH of 2 to 5. When contacting living earthworms withhydroxycarboxylic acid after contact with a metal chloride, it ispreferable that the contact with hydroxycarboxylic acid be carried outpromptly after the contact with the chloride of the metal. It ispreferable to wash the living earthworms with water before the contactwith the hydroxycarboxylic acid. By contacting the earthworms withhydroxycarboxylic acid after the removal of the chloride of the metalthrough water washing, earthworm dry powder having high enzyme activityis obtained. In the case of washing a metal chloride with water prior tocontact with hydroxycarboxylic acid, the washing should be carried outpreferably within 30 minutes, more preferably within 20 minutes afterthe start of contact with the metal chloride. The washing method is notparticularly limited, and a known method can be adopted.

When living earthworms are kept in contact with hydroxycarboxylic acidpowder for a long time, they die, they lose their living functions, anddo not excrete intestinal contents in the gastrointestinal tract, andtherefore, it is preferable to adjust the pH to 2 to 5 by diluting thehydroxycarboxylic acid with water as soon as possible, preferably within30 seconds, more preferably within 20 seconds.

Because hydroxycarboxylic acid forms an unpleasant living environmentfor earthworms, living earthworms try to improve the living environmentby releasing body fluids and excreta by self-preservation instinct.Since hydroxycarboxylic acid has bactericidal properties,hydroxycarboxylic acid plays a role of promoting the earthworms toexcrete intestinal contents and the like remaining in the digestiveorgan as described above, and hydroxycarboxylic acid can be expected tohave an effect of sterilizing germs attached to the earthworms.

The crystalline hydroxycarboxylic acid used in the above-describedmethod can be used irrespective of the number of hydroxy groups or thenumber of carboxyl groups as long as the crystalline hydroxycarboxylicacid shows a crystalline form under the conditions of use. In otherwords, any of monohydroxy monocarboxylic acid, monohydroxypolycarboxylic acid, polyhydroxy monocarboxylic acid and polyhydroxypolycarboxylic acid may be used.

Examples of the hydroxycarboxylic acid include glycolic acid, lacticacid, acetic acid, β-hydroxypropionic acid, α-hydroxy-n-butyric acid,β-hydroxy-n-butyric acid, α-hydroxy-n-valeric acid, β-hydroxy-n-valericacid, malic acid, α-methyl malic acid, α-hydroxy glutaric acid,β-hydroxy glutaric acid, citric acid, malonic acid, and succinic acid.Among them, lactic acid, acetic acid, malic acid, citric acid, malonicacid, and succinic acid are preferable because they can be used for foodand are easily available. The hydroxycarboxylic acid may be used singlyor two or more thereof may be used in a mixture.

Water accounts for 65% of the tissues of a living earthworm. There is acertain amount of time while the life-keeping function of a livingearthworm lasts, but as the living earthworm dies, an enzyme works, andtherefore, it is necessary to carefully control the time to leave theliving earthworm in an uncomfortable living environment. Although suchtime depends on conditions, it is usually in a range of 3 to 180minutes.

It is preferable that a living body of an earthworm treated withhydroxycarboxylic acid is washed with water and then milled to obtain aliquid or pasty milled matter. The washing is preferably performed withpure water. The washing method is not particularly limited, and a knownwater washing method can be adopted. The total time of a treatmentprocess before milling, that is, the time from the sprinkling of a metalchloride on living earthworms to the completion of removal ofhydroxycarboxylic acid by washing with water is preferably within 240minutes.

The above-described milling method is not particularly limited, and forexample, milling is carried out usually at 1 to 25° C. using, forexample, a homogenizer, a blender, a homomixer, a grinder or a Douncehomogenizer. From the viewpoint of suppressing decomposition ofearthworm components, it is preferable to carry out the milling at lowtemperature, and a temperature of 2 to 15° C. is preferable.

A milled matter obtained by milling earthworms are placed on a stainlesssteel tray or the like and subjected to freeze drying. At this time,since an enzyme contained in a living body of earthworm does not act onliving cells but acts instantaneously on dead cells, there is apossibility that a putrefactive gas may be generated. In order toprevent this, it is preferable to instantaneously quench and freeze to−18° C. to −35° C. to suppress the action of the enzyme and then performfreeze-drying.

As described above, it is preferable to quickly freeze earthworms inorder to make the earthworms into powder without impairing the inherentpharmacological action of the earthworms, but on the other hand, whenthe milled earthworms are frozen in a very short time, impurities thatare present together with protein, which is the main component of anearthworm paste, form a spot-like unfrozen part, and may not beseparated, and therefore, excessively rapid freezing is not preferable.Therefore, the freezing is preferably carried out at a low temperatureof −18° C. to −35° C. for 20 to 240 hours, and more preferably 50 to 170hours.

When performing the freeze-drying, it is important to choose theconditions under which moisture and impurities can be removed withoutremaining. For that purpose, it is preferable to control that thefreeze-drying is performed under a pressure of 50 Pa or lower whileincreasing the temperature stepwise in a range of −60° C. to +90° C. for10 to 60 hours.

In a method of the freeze-drying, for example, as described above, aftera milled matter is frozen at a temperature of −18° C. to −35° C. for 20to 240 hours, the temperature is then raised in several steps at atemperature of −60° C. to +90° C., and the milled matter is frozenvacuum dried for 10 to 60 hours while reducing the pressure in severalstages at a pressure of 25 to 40 Pa, whereby a light yellow earthwormdry powder in a sterile state can be obtained.

Furthermore, it is preferable to include a step of dissolving the milledmatter in a freeze-dried form in water or an aqueous ethanol solutionand removing or separating an insoluble fraction. The step of removingor separating an insoluble fraction can be carried out as in the abovethrough precipitation by leaving, centrifugation, filtration or thelike. A step of dissolving the freeze-dried milled matter in water or anaqueous ethanol solution is preferably carried out with stirring orshaking. Time required for the dissolution is preferably 1 to 120minutes, and more preferably 5 to 80 minutes. An ethanol concentrationof the aqueous ethanol solution is not particularly limited; but it ispreferably 10 to 70% (v/v), and more preferably 30 to 60%.

As an earthworm extract, a supernatant of a solution obtained bydissolving the freeze-dried earthworm milled matter in water or anaqueous ethanol solution as described above may be used as it is in theform of an aqueous solution, may be used as a concentrate afterevaporating water therefrom, or may also be used in the form of powderby drying. A powder obtained by drying the supernatant may be dissolvedin water and used. Alternatively, a powder obtained by freeze-drying anearthworm paste may be used as it is without being dissolved in water oran aqueous ethanol solution.

In the removal method for removing intestinal contents of an earthwormand dirt adhered to an earthworm skin, prior to a process of placingliving earthworms in an unpleasant environment, that is, before bringingthe living earthworms into contact with a metal chloride orhydroxycarboxylic acid, it is preferable that the living earthworms areplaced in a flat box like a bread box, and that the living earthwormsare left to stand for 10 to 50 hours in a light place to remove dirtadhering to their skin. The time to leave the living earthworms in thelight place is more preferably 12 to 24 hours. In this process, theamount of the earthworms contained in the flat box is preferably such anamount that the earthworms are piled up to a thickness of 30 to 60 mm,and preferably 40 to 50 mm. It is preferable that there is no foreignmatter such as sand or mud in this flat box, and since earthworms arenocturnal, living activities become active in dark places and earthwormsmay exhaust their physical strength, and therefore, keeping the interiorof the flat box bright at night using an electric light culture methodor the like is preferable. By this treatment, the living earthwormsexert self-defense instinct and try to maintain the environment byexcreting contents remaining in their gastrointestinal tracts, coveringtheir entire body with these excreta, and thereby preventing evaporationof moisture. Thus, by repeatedly peeling off the dirt, namely excreta,covering the earthworms by appropriate means, it is possible to finallyeliminate the contents in the gastrointestinal tract of the earthwormsand the dirt adhering to the skin.

Peeling off of the dirt adhering to the skins of earthworms can becarried out, for example, by covering the living earthworms with anonwoven fabric and adsorbing the dirt on the fabric. By combining:leaving the earthworm in the light place and removing the dirt adheringto the skins; and bringing the living earthworms into contact with achloride of the above-described metal and/or hydroxycarboxylic acid,further excretion and removal of toxic substances from the earthwormbodies can be expected.

In the present invention, as a method for obtaining dry earthwormpowder, the following methods are preferable particularly from theviewpoint of storage stability of the resulting dry powder.

(A-1) A method for producing dry earthworm powder including steps of:

-   -   bringing a living earthworm into contact with a chloride of at        least one metal selected from the group consisting of potassium,        sodium, magnesium, and calcium,    -   subsequently bringing the living earthworm into contact with a        powdery hydroxycarboxylic acid, diluting the hydroxycarboxylic        acid with water to adjust the pH to 2 to 5, leaving the        earthworm in the diluted hydroxycarboxylic acid for 3 to 180        minutes, washing the earthworm with water, milling the        earthworm, and freeze-drying the obtained milled matter.

(A-2) A method for producing dry earthworm powder including steps of:

-   -   bringing a living earthworm into contact with a chloride of at        least one metal selected from the group consisting of potassium,        sodium, magnesium, and calcium,    -   subsequently immersing the living earthworm in a        hydroxycarboxylic acid aqueous solution in which the pH is        adjusted to 2 to 5, leaving the earthworm in the solution for 3        to 180 minutes, washing the earthworm with water, milling the        earthworm, and freeze-drying the obtained milled matter.

(A-3) A method for producing a dry earthworm powder further including inthe (A-1) or (A-2) steps of: dissolving the freeze-dried milled matterin water or an aqueous ethanol solution, removing or separating aninsoluble fraction therefrom, and then further freeze-drying theobtained solution.

After freeze-drying the milled matter obtained by grinding the livingearthworm, the dried product obtained may be heat-treated from theviewpoint of sterilization of the dried product. The temperature of theheat treatment is preferably 110° C. or more and less than 130° C. Whenthe heating temperature is lower than 110° C., sterilization of thedried product may be insufficient, and when the heating temperature is130° C. or higher, an enzyme contained in the dried earthworm product isdeactivated and the activity is unfavorably lowered. More preferably,the heating temperature is 115 to 125° C. The heating method is notparticularly limited, and examples thereof include a method of applyinghot air, a method of using a heating jacket, a method of heating thesubject on a tray or the like using a heater, and a method using athermostat incubator. The heating time is preferably 30 seconds to 130minutes, more preferably 30 minutes to 90 minutes, and still morepreferably 60 minutes to 90 minutes. When the heating time is too short,sterilization may be insufficient, and when the heating time is toolong, the activity of the enzyme will be lost, which is not preferable.Since the enzymatic activity is lost when the enzyme in the liquid issubjected to the heat treatment, it is preferable to perform the heattreatment on the dry earthworm powder.

In the present invention, as a method for obtaining a milled matter ofan earthworm, the following methods are preferable.

(B-1) A method for producing a milled matter of an earthworm includingsteps of:

-   -   bringing a living earthworm into contact with a chloride of at        least one metal selected from the group consisting of potassium,        sodium, magnesium, and calcium,    -   subsequently bringing the living earthworm into contact with a        powdery hydroxycarboxylic acid, diluting the hydroxycarboxylic        acid with water to adjust the pH to 2 to 5, leaving the        earthworm in the diluted hydroxycarboxylic acid for 3 to 180        minutes, washing the earthworm with water, and milling the        earthworm.

(B-2) A method for producing a milled matter of an earthworm includingsteps of:

-   -   bringing a living earthworm into contact with a chloride of a        metal selected from the group consisting of potassium, sodium,        magnesium, and calcium,    -   subsequently immersing the living earthworm in a        hydroxycarboxylic acid aqueous solution in which the pH is        adjusted to 2 to 5, leaving the earthworm in the solution for 3        to 180 minutes, washing the earthworm with water, and milling        the earthworm.

As a method for obtaining an extract of an earthworm, the followingmethods are preferable.

(C-1) A method for producing an extract of an earthworm including stepsof:

-   -   bringing a living earthworm into contact with a chloride of at        least one metal selected from the group consisting of potassium,        sodium, magnesium, and calcium,    -   subsequently bringing the living earthworm into contact with a        powdery hydroxycarboxylic acid, diluting the hydroxycarboxylic        acid with water to adjust the pH to 2 to 5, leaving the        earthworm in the diluted hydroxycarboxylic acid for 3 to 180        minutes, washing the earthworm with water, milling the        earthworm, dissolving the obtained milled matter in a        freeze-dried form in water or an aqueous ethanol solution, and        removing or separating an insoluble fraction.

(C-2) A method for producing an extract of an earthworm including thesteps of:

-   -   bringing a living earthworm into contact with a chloride of a        metal selected from the group consisting of potassium, sodium,        magnesium, and calcium,    -   subsequently immersing the living earthworm in a        hydroxycarboxylic acid aqueous solution in which the pH is        adjusted to 2 to 5, leaving the earthworm in the solution for 3        to 180 minutes, washing the earthworm with water, milling the        earthworm, dissolving the obtained milled matter in a        freeze-dried form in water or an aqueous ethanol solution, and        removing or separating an insoluble fraction from the obtained        solution.

Although the blending amount of dry powder, milled matter, and/orextract of an earthworm is not particularly limited, in the case of aliquid nasal drop composition, for example, the blending amount is, per100 L of the nasal drop composition in terms of dry mass of the extractextracted with water, 0.1 to 100 mg, preferably 0.2 to 50 mg, and morepreferably 1 to 20 mg.

EXAMPLES

Hereinbelow, the present invention will be described more specificallywith reference to Examples. However, the present invention is notintended to be limited by Examples below. In Examples below, “percent(%)” is by mass unless otherwise specified.

(Aqueous Organic Substance Decomposition Product)

Forty liters of water was introduced into a reaction vessel containing40 kg of earthworm Lumbricus rubellus castings and 15 kg of a woodmaterial (Japanese cedar) (5 kg of woodchips and 10 kg of a blend ofwood dusts and rice hulls), and then vaporized water was collected by adehumidifier (DM-30, manufactured by Nakatomi Corporation) attached tothe reaction vessel for about 1 day while stirring to obtain 15 to 20 Lof a liquid. Ten to twenty liters of water was further added to thereaction vessel, then 10 kg of a wood material (Japanese cedar) (5 kg ofwoodchips and 5 kg of a blend of wood dusts and rice hulls) was addedthereto, and then vaporized water was collected by the dehumidifier forabout 1 day in the same manner to obtain 15 to 20 L of a liquid. About40 L of a liquid (pH 8.71) prepared by mixing the obtained liquids wasused as an aqueous organic substance decomposition product.

In the production of the above-described aqueous organic substancedecomposition product, the water used was water prepared by purifyingtap water with an SPG (Shirasu porous glass) permeable membrane (SPGTechnology Co., Ltd.) and activated carbon.

(Earthworm Extract)

After leaving for 24 hours in a light place, 30 kg of living Lumbricusrubellus of which dirt was peeled from the skins were spread out toabout 5 cm in the thickness on a flat plate, and 250 g of sodiumchloride was evenly sprinkled on top of the earthworms. After 20minutes, the earthworms were washed with water. Thereafter, 250 g ofcitric acid was sprinkled on the earthworms in the same manner, and thenthe citric acid was diluted by adding 30 liters of pure water in 15seconds. At this time, the pH immediately after addition of water was2.25, and the pH when completely diluted was 2.74. When sprinkled withcitric acid powder, the earthworms released yellow body fluid at once.After the dilution of the citric acid with water, the earthworms werekept for 20 minutes in that state. Subsequently, the living earthwormswere taken out from the soiled citric acid aqueous solution, washed withwater, and milled at 10° C. using a homogenizer to prepare an earthwormpaste. Next, after sucking and deaerating the earthworm paste to removea gas contained therein, the earthworm paste was then placed on astainless steel tray, instantaneously cooled to −35° C., and graduallyfrozen for 50 hours while maintaining this temperature. The frozenearthworm paste was kept at −35° C. and 0 Pa for 2 hours, thetemperature was then raised to 25° C. at 40 Pa for 10 hours, thetemperature was then raised to 40° C. at 35 Pa for 14 hours, thetemperature was then raised to 65° C. at 35 Pa for 12 hours, andfinally, the temperature was raised to 80° C. at 25 Pa for 6 hours toperform vacuum freeze drying. By this treatment, light yellow dryearthworm powder having a water content of 8% by mass was obtained.

25 g of the dry earthworm powder obtained as above was sampled, 500 mLof distilled water was added thereto, and the mixture was stirred atroom temperature for 1 hour and extracted. The obtained extract wascentrifuged (10,000×g, 4° C., 15 minutes), and a supernatant wascollected to obtain an earthworm extract. The obtained earthworm extractwas finely pulverized with a freeze vacuum dryer, sampled by 30 mg, anddiluted with 500 mL of distilled water to obtain a stock solution.

(Nasal Drop Composition)

The aqueous organic substance decomposition product obtained above wasdiluted 5 times with water. The water used for the dilution was waterprepared by purifying tap water with an SPG (Shirasu porous glass)permeable membrane (SPG Technology Co., Ltd.) and activated carbon.

The diluted aqueous organic substance decomposition product and thediluted stock solution of the earthworm extract obtained above weremixed at a ratio of 1,000:1 and passed through a 0.2 μm filter to obtaina nasal drop composition.

Example 1 <Pollinosis 1>

The symptoms of pollinosis of the subject below who was sprayed in thenasal cavities with the nasal drop composition obtained above in theform of mist 6 to 10 times per day, 2 to 5 sprays per application usinga commercially available nasal irrigation spray on a daily basis wereobserved.

-   -   Subject: Female, 22 years old, disease duration: 2 years.    -   After 3 days, runny nose and tears decreased.    -   After 7 days, runny nose and tears stopped.    -   After 15 days, pain of pollinosis alleviated.    -   After 30 days, cured.

Example 2 <Pollinosis 2>

The symptoms of pollinosis of the subject below who was sprayed in thenasal cavities with the nasal drop composition obtained above in theform of mist 6 to 10 times per day, 2 to 5 sprays per application usinga commercially available nasal irrigation spray on a daily basis wereobserved.

-   -   Subject: Male, 52 years old, disease duration: 15 years.    -   After 7 days, runny nose and eye itching decreased.    -   After 14 days, runny nose and itching disappeared.    -   After 25 days, the symptoms improved.    -   After 30 days, the symptoms disappeared.

Example 3 <Empyema 1>

The symptoms of empyema of the subject below who was sprayed in thenasal cavities with the nasal drop composition obtained above in theform of mist 6 to 10 times per day, 2 to 5 sprays per application usinga commercially available nasal irrigation spray on a daily basis wereobserved.

-   -   Subject: Male, 18 years old, disease duration: 2 months, yellow        runny nose.    -   After 7 days, amount and color of runny nose decreased.    -   After 10 days, runny nose stopped.    -   After 25 days, stuffy nose cleared, and the empyema cured.

Example 4 <Empyema 2>

The symptoms of empyema of the subject below who was sprayed in thenasal cavities with the nasal drop composition obtained above in theform of mist 6 to 10 times per day, 2 to 5 sprays per application usinga commercially available nasal irrigation spray on a daily basis wereobserved.

-   -   Subject: Female, 15 years old, disease duration: 1 month.    -   After 3 days, runny nose decreased.    -   After 7 days, runny nose stopped.    -   After 15 days, stuffy nose cleared, and the empyema cured.

As shown in Examples 1 to 4, it was confirmed that a nasal dropcomposition suitable for treating or preventing a disease or symptom inthe nasal cavities can be produced by collecting evaporated watergenerated from a mixture of earthworm castings and water.

1-10. (canceled)
 11. A method of treating or preventing a disease orsymptom in a nasal cavity, comprising administering a nasal dropcomposition produced by a production method comprising: mixing earthwormcastings with water to obtain a mixture; and collecting vaporized watergenerated from the mixture to obtain a liquid as the nasal dropcomposition.
 12. The method according to claim 11, wherein the mixingfurther comprises mixing an organic substance together with theearthworm castings and the water.
 13. The method according to claim 12,wherein the organic substance is a wood material.
 14. The methodaccording to claim 11, wherein the production method further comprisesdiluting the liquid with water to obtain the nasal drop composition. 15.The method according to claim 11, wherein the disease or symptom in thenasal cavity is pollinosis or empyema.